Birbeck granules (BG) are cytoplasmic organelles that are only found in Langerhans cells (LC). The function of BG is still unclear, although it has been claimed that they are actively involved in receptor-mediated endocytosis and participate in the antigen-processing/presenting function of LC. We have identified a healthy white 29-year-old man whose LC completely lack the presence of BG as determined by electronmicroscopic studies. This was observed repeatedly using skin biopsy specimens taken from several places on the body during a period of 2.5 years. The absence of BG in these LG was documented further by the lack of staining with a BG-specific monoclonal antibody. Despite the complete lack of BG, LC were present in normal numbers, had all the usual morphologic characteristics, and were CD1a and human leukocyte antigen (HLA) class II positive. Two observations indicate that these BG-negative LC display normal antigen-presenting capacity. First, the individual could be sensitized by the hapten diphenylcyclopropenone. This was accompanied by a strong increase in the cell surface expression of HLA class II antigens on his LC, suggesting LC activation. Second, his epidermal cells elicited a normal positive response in an allogeneic mixed epidermal cell lymphocyte reaction. Together these observations strongly suggest that BG are not a prerequisite for normal LC function in vivo and in vitro.